Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease, occurring in 1 in 500 people. For some young patients, the first sign is sudden death. Septal hypertrophy leads to obstruction of the left ventricular outflow path and about one-third of patients with obstruction remain symptomatic after pharmacological therapy. Presently available treatments to reduce obstruction are open heart surgery for septal myectomy and transcatheter septal ablation with alcohol. The less invasive alcohol ablation procedure unfortunately has a high incidence of serious complications and is not widely applied. A completely new non-invasive option for tissue reduction is sorely needed for HCM and potentially other myocardial hypertrophies. The objective of this project is to create a safer, gentler method of myocardial reduction for HCM. Myocardial contrast echocardiography (MCE) has enabled visualization of myocardial perfusion by imaging strong echos from contrast-agent microbubbles. For high amplitude MCE, intermittent destruction of contrast microbubbles has been shown to lethally injure cardiomyocytes by the cavitation mechanism, which leads to randomly scattered microlesions seen in histology. The central hypothesis driving this project is that the microlesioning effect seen in diagnostic MCE can be enhanced to achieve therapeutically efficacious cardiac reduction. Echocardiography together with electrocardiography is the gold standard for diagnosis and treatment follow-up for HCM. The potential breakthrough resulting from fusion of enhanced diagnostic MCE with controlled microlesioning, for therapeutic MCE (TMCE), creates a compelling rationale for this project. Our research strategy has three specific aims: (1) enhance microlesioning by MCE for efficacious myocardial reduction with monitoring of cavitation emissions, (2) develop an ultrasonic system with TMCE capability and treatment feedback and (3) demonstrate the safety and efficacy of therapeutic myocardial reduction by TMCE in a realistic porcine model. Although the possibility of MCE for HCM therapy was conceivable in 2005, three developments have coalesced to make the idea practical: the development of integrated cavitation emissions as a monitoring method for accumulated bioeffects, the realization that premature complexes in the ECG report the microlesion threshold regardless of in situ attenuation, and the availability of new platforms for ultrasound system development. The outcomes expected from achieving our aims are a safe and efficacious protocol for TMCE, an ultrasonic machine fusing imaging with therapeutic treatment, and the proof of principle for this breakthrough therapy. The overall impact of this project will be the advent of a minimally invasive new tool for myocardial reduction therapy. This innovative technology will advance medical ultrasonics and improve significantly the prognosis for patients living with life-threatening myocardial hypertrophy.